This application is a Rule 371 Application of PCT Application No. EP00/13001, filed Dec. 20, 2000, which claims priority to GB Application Serial No. 9930358.8, filed Dec. 22, 1999.
This invention relates to a process for the preparation of pyrazolopyridazine derivatives and to intermediates for use therein.
Pyrazolopyridazine derivatives of formula (I) 
and pharmaceutically acceptable derivatives thereof in which:
R0 is halogen, C1-6-alkyl, C1-6alkoxy, C1-6alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR4R5;
R1 and R2 are independently selected from H, C1-6alkyl, C1-6alkyl substituted by one or more fluorine atoms, C1-6alkoxy, C1-6hydroxyalkyl, SC1-6alkyl, C(O)H, C(O)C1-6alkyl, C1-6-alkylsulphonyl, C1-6alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2C1-6alkyl, O(CH2)nSC1-6alkyl, (CH2)nNR4R5, (CH2)nSC1-6alkyl or C(O)NR4R5; with the proviso that when R0 is at the 4-position and is halogen, at least one of R1 and R2 is C1-6alkylsulphonyl, C1-6-alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2C1-6alkyl, O(CH2)nSC1-6alkyl, (CH2)nNR4R5 or (CH2)nSC1-6alkyl, C(O)NR4R5;
R3 is C1-6alkyl or NH2;
R4 and R5 are independently selected from H, or C1-6alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring;
and n is 1-4;
are disclosed in international patent application publication no. WO99/12930, incorporated herein by reference.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester, of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.
Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
The term halogen is used to represent fluorine, chlorine, bromine or iodine.
The term xe2x80x98alkylxe2x80x99 as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
The compounds of formula (I) are potent and selective inhibitors of COX-2. They are of interest for use in human and veterinary medicine, particularly in the treatment of the pain (both chronic and acute), fever and inflammation of a variety of conditions and diseases.
Several processes for the preparation of the compounds of formula (I) are disclosed in WO99/12930.
The present invention provides a particularly advantageous process of preparing compounds of formula (I), not hitherto specifically disclosed, which comprises oxidation of a corresponding dihydro-pyrazolopyridazine.
Accordingly, in a first aspect, the instant invention provides a process for the preparation of a compound of formula (I) which comprises oxidising under conventional conditions a compound of formula (II) 
wherein R0 to R3 are as defined for formula (I).
Conveniently the oxidation is effected in a solvent, such as a halogenated alkane (e.g. dichloromethane); at ambient to elevated temperature, such as from 20xc2x0 C. to reflux (e.g. at about 25xc2x0 C.); and in the presence of a catalyst, such as activated carbon, or a transition metal catalyst (e.g. palladium on activated carbon). Alternatively, the catalyst may be replaced by an oxidising agent, such as a source of oxygen (e.g. air), or iodine.
The process according to the invention is surprisingly advantageous, being easy to carry out and proceeding in good yield.
As will be appreciated by those skilled in the art, the preparation of pharmaceutically acceptable derivatives of formula (I) may conveniently be effected by a process which comprises oxidising under conventional conditions a corresponding derivative of formula (II).
In another aspect the invention provides a process for preparing a compound of formula (I) where R0 is at the 3- or 4-position of the phenyl ring, as defined in formula (I).
In another aspect the invention provides a process for preparing a compound of formula (I) where R1 is at the 6-position of the pyridazine ring, as defined in formula (I).
In another aspect the invention provides a process for preparing a compound of formula (I) where R0 is F, C1-3alkyl, C1-3alkoxy, C1-3alkoxy substituted by one or more fluorine atoms, or O(CH2)1-3NR4R5; or, more preferably, R0 is F, C1-3alkoxy or C1-3alkoxy substituted by one or more fluorine atoms.
In another aspect the invention provides a process for preparing a compound of formula (I) where R1 is C1-4alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms, O(CH2)1-3CO2C1-4alkyl, O(CH2)1-3SC1-4alkyl, (CH2)1-3NR4R5, (CH2)1-3SC1-4alkyl or C(O)NR4R5 or, when R0 is C1-6alkyl, C1-6alkoxy, O(CH2)nNR4R5, may also be H; or, more preferably, R1 is C1-4alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms or, when R0 is C1-6alkyl, C1-6alkoxy, C1-6alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR4R5, may also be H.
In another aspect the invention provides a process for preparing a compound of formula (I) where R2 is H.
In another aspect the invention provides a process for preparing a compound of formula (I) where R3 is methyl or NH2.
In another aspect the invention provides a process for preparing a compound of formula (I) where R4 and R5 are independently C1-3alkyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring.
In another aspect the invention provides a process for preparing a compound of formula (I) where n is 1-3, more preferably 1 or 2.
In another aspect the invention provides a process for preparing one group of compounds of formula (I) (group A) wherein: R0 is F, C1-3alkyl, C1-3alkoxy, C1-3alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR4R5; R1 is C1-4alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2C1-4alkyl, O(CH2)nSC1-4alkyl, (CH2)nNR4R5, (CH2)nSC1-4alkyl or C(O)NR4R5 or, when R0 is C1-3alkyl, C1-3alkoxy, C1-3alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR4R5, may also be H; R2 is H; R3 is methyl or NH2; R4 and R5 are independently C1-3alkyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring; and n is 1-3.
In another aspect the invention provides a process for preparing another group of compounds (group A1) wherein R0 is F, methyl, C1-2alkoxy, OCHF2, or O(CH2)nNR4R5; R1 is methylsulphonyl, OCHF2, O(CH2)nCO2C1-4alkyl, O(CH2)nSCH3, (CH2)nNR4R5, (CH2)nSCH3 or C(O)NR4R5 or, when R0 is methyl, C1-2alkoxy, OCHF2, or O(CH2)nN(CH3)2, may also be H; R2 is H; R3 is methyl or NH2; R4 and R5 are both methyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring; and n is 1-2.
In another aspect the invention provides a process for preparing a compound of formula (I) within group (group A2) wherein R0 is F, C1-3alkoxy or C1-3alkoxy substituted by one or more fluorine atoms; R1 is C1-4alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms or, when R0 C1-3alkoxy or C1-3alkoxy substituted by one or more fluorine atoms, may also be H; R2 is H; and R3 is methyl or NH2.
In another aspect the invention provides a process for preparing a compound of formula (I) within groups A, A1 and A2, wherein R0 is preferably at the 3- or 4-position of the phenyl ring and R2 is at the 6-position of the pyridazine ring.
In another aspect the invention provides a process for preparing the compound 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine and pharmaceutically acceptable derivatives thereof.
Compounds of formula (II), including derivatives corresponding to pharmaceutically acceptable derivatives of formula (I), may be prepared by any method known in the art for the preparation of compounds of analogous structure.
The present invention provides a particularly advantageous process for the preparation of compounds of formula (II), as illustrated in Scheme 1 that follows. The reaction conditions and reagents mentioned in Scheme 1 are by way of example only. In scheme 1, R0 to R3 are as defined for formula (I) above; Ph is phenyl; and Xxe2x88x92 is a counterion. 
Ref 1 H. Zimmer, J. P. Bercz, Liebigs Ann. Chem. 1965, 686, 107-114, incorporated herein by reference.
Ref 2 Friedel Crafts acylation in the presence of a Lewis acid (e.g. AlCl3).
Ref 3 Suitable inorganic bases include alkali hydroxides (e.g. NaOH); suitable organic bases include amines (e.g. N,N,N,N-tetramethylethylenediamine).
It will be appreciated by those skilled in the art that the imines of formula (III) prepared from the ethanones of formula (V) need not necessarily be isolated and may be employed in situ in the preparation of compounds of formula (II).
The compounds of formula (II) themselves need not necessarily be isolated and may be employed in situ in the preparation of compounds of formula (I), as described hereinabove.
Counterion Xxe2x88x92 in the N-aminopyridazinium salts of formula (IV) is conveniently a halide (e.g. Ixe2x88x92) or, more preferably, hexafluorophosphate (PF6xe2x88x92). N-Aminopyridazinium hexafluorophosphate salts of formula (IV) are novel and their use according to Scheme 1 is surprisingly advantageous. Thus N-aminopyridazinium hexafluorophosphate salts of formula (IV) are easily prepared and enable the conversion of ethanones of formula (V) to compounds of formula (II) via imines of formula (III) to proceed easily and in high yield.
Accordingly, in a further aspect the invention provides N-aminopyridazinium hexafluorophosphate salts of formula (IV) wherein R0 to R3 are as defined for formula (I) above, in particular N-aminopyridazinium hexafluorophosphate.
It will be appreciated by those skilled in the art that compounds of formula (II) may exist as a number of isomers, for example, as follows: 
It will be further appreciated by those skilled in the art that such isomers may under certain conditions exist as an equilibrating mixture.
It will be still further appreciated by those skilled in the art that the compounds of formula (II) contain at least one chiral centre, designated by * therein, and that such compounds exist in the form of a pair of optical isomers (i.e. enantiomers).
It is to be understood that the present invention encompasses all isomers of the compounds of formula (II) and pharmaceutically acceptable derivatives thereof, including all positional, geometric, tautomeric, optical and diastereomeric forms, and mixtures thereof (e.g. racemic mixtures).
N-Aminopyridazinium halides of formula (IV) are either known compounds or may be prepared by literature methods such as those described in, for example, Y Kobayashi et al, Chem Pharm Bull, (1971), 19(10), 2106-15; T. Tsuchiya, J. Kurita and K. Takayama, Chem. Pharm. Bull. 28(9) 2676-2681 (1980); and K Novitskii et al, Khim Geterotskil Soedin, 1970 2, 57-62; all incorporated herein by reference.
N-Aminopyridazinium hexafluorophosphates of formula (IV) may be prepared by reacting the corresponding N-aminopyridazinium sulphate with hexafluorophosphoric acid or a suitable salt thereof (e.g. potassium hexafluorophosphate or ammonium hexafluorophosphate). The aforementioned sulphates may be prepared from pyridazine by conventional means.
Compounds of formula (VII) are either known compounds or may be prepared by literature methods such as those described in, for example, H Forrest, A Fuller, J Walker, J Chem Soc., 1948, 1501; R Dohmori, Chem Pharm Bull., 1964, (12), 591; and R Bromilow, K Chamberlain, S Patil, Pestic. Sci., 1990, (30), 1.
Compounds of formulae (VII), (VIII) and (X) are either known compounds or may by prepared from known compounds by conventional chemistry.
As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions.
The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Theodora W. Green and Peter G M Wuts, second edition, (John Wiley and Sons, 1991), incorporated herein by reference, which also describes methods for the removal of such groups.
Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein form further aspects of the present invention. Compounds of formula (II), (III) and (V), especially those compounds wherein R0 is ethoxy, R1 and R2 are H, and R3 is methyl, are key intermediates and represent a particular aspect of the present invention.
Conveniently, compounds of formula (I) are isolated following work-up in the form of the free base. Pharmaceutically acceptable acid addition salts of the compounds of formula (I) may be prepared using conventional means.
Solvates (e.g. hydrates) of a compound of formula (I) may be formed during the work-up procedure of one of the aforementioned process steps.
When a particular isomeric form of a compound is desired the required isomer may conveniently be separated using preparative high performance liquid chromatography (h.p.l.c.).